PROJECT SUMMARY: The "nearest-neighbor recognition" (NNR) method is a promising chemical technique that provides fundamental insight into the lateral organization of fluid phospholipid membranes. In essence, NNR measurements take molecular-level snapshots of membrane organization by detecting and quantifying the tendency of lipids to become nearest-neighbors. The specific aims of this research are to use the NNR method to investigate lipid-peptide interactions, lipid-protein interactions, and lipid-lipid interactions in the presence of natural and unnatural membrane-perturbing agents. More specifically, lipid-peptide experiments will be part of a long-term effort aimed at clarifying the "rules" governing the sorting of peripheral and integral proteins by lipids in fluid bilayers. Lipid-protein studies, in combination with transbilayer phospholipid interactions, will provide insight into a much-debated issue that has a direct bearing on the structure and function of cell membranes-an issue for which there is virtually no experimental data;that is, the "communication" between the inner and outer leaflets of lipid bilayers. Finally, the effects of selected general anesthetics and amyloid beta-peptides on lipid-lipid interactions will provide fundamental insight into two problems that have major biomedical importance;that is, the mechanism by which general anesthetics function, and the molecular basis of Alzheimer's disease. The long-term objective of this program is to develop a fundamental understanding of the two-dimensional organization of fluid bilayers, which will help bring exploitable targets in biological membranes into sharper focus. Such insight will assist the rational design of novel classes of therapeutic agents. RELEVANCE: Cell membranes are "the skin" of cells, which are essential for maintaining the living state. Understanding how these membranes are organized in two dimensions, at the molecular level, should aid in the design of new and improved drugs;e.g., drugs that can be used to cure Alzheimer's disease, drugs to combat alcohol abuse, and drugs that can be used as improved general anesthetics. This program is aimed at obtaining such an understanding using simple model systems.